1-16148628-C-T

Variant names:

• chr1-16148628-C-T
• rs6678616
• NM_004431.5:c.573G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004431.5(EPHA2):​c.573G>A​(p.Leu191Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,607,608 control chromosomes in the GnomAD database, including 86,756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6602 hom., cov: 33)
  • Exomes 𝑓: 0.32 (80154 hom.)
• Consequence: EPHA2 NM_004431.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.414
• Publications: 24 publications found

Genes affected

EPHA2 (HGNC:3386): (EPH receptor A2) This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene encodes a protein that binds ephrin-A ligands. Mutations in this gene are the cause of certain genetically-related cataract disorders.[provided by RefSeq, May 2010]

EPHA2 Gene-Disease associations (from GenCC):

• cataract 6 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• early-onset non-syndromic cataract

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior subcapsular cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-16148628-C-T is Benign according to our data. Variant chr1-16148628-C-T is described in ClinVar as Benign. ClinVar VariationId is 259394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.414 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.573G>A	p.Leu191Leu	synonymous_variant	Exon 3 of 17	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.573G>A	p.Leu191Leu	synonymous_variant	Exon 3 of 17	1	NM_004431.5	ENSP00000351209.5
EPHA2	ENST00000461614.1	n.625G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42280 AN: 151972 Hom.: 6594 Cov.: 33

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.298 AC: 73530 AN: 246468 AF XY: 0.306

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.332

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.0176

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.328

GnomAD4 exome AF: 0.324 AC: 472241 AN: 1455518 Hom.: 80154 Cov.: 84 AF XY: 0.326 AC XY: 236464 AN XY: 724360

African (AFR) AF: 0.166 AC: 5571 AN: 33478

American (AMR) AF: 0.331 AC: 14783 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 10512 AN: 26134

East Asian (EAS) AF: 0.0238 AC: 945 AN: 39700

South Asian (SAS) AF: 0.338 AC: 29155 AN: 86244

European-Finnish (FIN) AF: 0.278 AC: 13161 AN: 47324

Middle Eastern (MID) AF: 0.450 AC: 2595 AN: 5768

European-Non Finnish (NFE) AF: 0.339 AC: 376377 AN: 1111844

Other (OTH) AF: 0.317 AC: 19142 AN: 60352

GnomAD4 genome AF: 0.278 AC: 42299 AN: 152090 Hom.: 6602 Cov.: 33 AF XY: 0.277 AC XY: 20598 AN XY: 74356

African (AFR) AF: 0.165 AC: 6855 AN: 41524

American (AMR) AF: 0.345 AC: 5273 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1394 AN: 3464

East Asian (EAS) AF: 0.0239 AC: 124 AN: 5186

South Asian (SAS) AF: 0.327 AC: 1581 AN: 4832

European-Finnish (FIN) AF: 0.273 AC: 2889 AN: 10580

Middle Eastern (MID) AF: 0.462 AC: 135 AN: 292

European-Non Finnish (NFE) AF: 0.340 AC: 23069 AN: 67932

Other (OTH) AF: 0.322 AC: 680 AN: 2110

Alfa AF: 0.312 Hom.: 6957

Bravo AF: 0.274

Asia WGS AF: 0.192 AC: 668 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 6 multiple types Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

May 01, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.3
DANN	Benign	0.92
PhyloP100		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6678616; hg19: chr1-16475123; COSMIC: COSV108188958; COSMIC: COSV108188958;